Hydrogen sulfide (H2S) is an endogenous gasotransmitter with cardioprotective and antiviral effects. In this work, new cysteine-selective nucleoside-H2S-donor hybrid molecules were prepared by conjugating nucleoside biomolecules with a thiol-activatable dithioacetyl group. 5'-Dithioacetate derivatives were synthesized from the canonical nucleosides (uridine, adenosine, cytidine, guanosine and thymidine), and the putative 5'-thio metabolites were also produced from uridine and adenosine. According to our measurements made with an H2S-specific sensor, nucleoside dithioacetates are moderately fast H2S donors, the guanosine derivative showed the fastest kinetics and the adenosine derivative the slowest. The antioxidant activity of 5'-thionucleosides is significantly higher than that of trolox, but lower than that of ascorbic acid, while intact dithioacetates have no remarkable antioxidant effect. In human Calu cells, the guanosine derivative showed a moderate anti-SARS-CoV-2 effect which was also confirmed by virus yield reduction assay. Dithioacetyl-adenosine and its metabolite showed similar acute cardiac effects as adenosine, however, it is noteworthy that both 5'-thio modified adenosines increased left ventricular ejection fraction or stroke volume, which was not observed with native adenosine.
- Klíčová slova
- Antioxidant, Antiviral, Dithioacetate, H2S donor, H2S release kinetics, Nucleoside, SARS-CoV-2,
- MeSH
- adenosin analogy a deriváty MeSH
- antioxidancia * farmakologie chemie MeSH
- antivirové látky * farmakologie chemická syntéza chemie MeSH
- buněčné linie MeSH
- farmakoterapie COVID-19 MeSH
- lidé MeSH
- nukleosidy farmakologie chemie metabolismus MeSH
- SARS-CoV-2 účinky léků metabolismus MeSH
- sulfan * metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- adenosin MeSH
- antioxidancia * MeSH
- antivirové látky * MeSH
- nukleosidy MeSH
- sulfan * MeSH
The synthesis and antiproliferative evaluation of novel d-glucopyranuronamide-containing nucleosides is described. Based on our previously reported anticancer d-glucuronamide-based nucleosides, new analogues comprising N/O-dodecyl or N-propargyl substituents at the glucuronamide unit and anomerically-N-linked 2-acetamido-6-chloropurine, 6-chloropurine or 4-(6-chloropurinyl)methyl triazole motifs were synthesized in 4-6 steps starting from acetonide-protected glucofuranurono-6,3-lactone. The methodologies were based on the access to N-substituted glycopyranuronamide precursors, namely 1,2-O-acetyl derivatives or glucuronoamidyl azides for further nucleobase N-glycosylation or 1,3-dipolar cycloaddition with N9 - and N7 -propargyl-6-chloropurines, respectively. N-Propargyl glucuronamide-based N9 -purine nucleosides were converted into (triazolyl)methyl amide-6,6-linked pseudodisaccharide nucleosides via cycloaddition with methyl 6-azido-glucopyranoside. A CuI/Amberlyst A-21 catalytic system employed in the cycloaddition reactions also effected conversion into 6-dimethylaminopurine nucleosides. Antiproliferative evaluation in chronic myeloid leukemia (K562) and breast cancer (MCF-7) cells revealed significant effects exhibited by the synthesized monododecylated purine-containing nucleosides. A N-propargyl 3-O-dodecyl glucuronamide derivative comprising a N9 -β-linked 6-chloropurine moiety was the most active compound against MCF-7 cells (GI50 =11.9 μM) while a related α-(purinyl)methyltriazole nucleoside comprising a N7 -linked 6-chloropurine moiety exhibited the highest activity against K562 cells (GI50 =8.0 μM). Flow cytometry and immunoblotting analysis of apoptosis-related proteins in K562 cells treated with the N-propargyl 3-O-dodecyl glucuronamide-based N9 -linked 6-chloropurine nucleoside indicated that it acts via apoptosis induction.
- Klíčová slova
- N-glycosylation, antiproliferative activity, cycloaddition, d-glucuronamide, nucleoside analogs,
- MeSH
- amidy * farmakologie MeSH
- glukuronáty MeSH
- lidé MeSH
- nukleosidy * farmakologie MeSH
- purinové nukleosidy MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- amidy * MeSH
- glucuronamide MeSH Prohlížeč
- glukuronáty MeSH
- nukleosidy * MeSH
- purinové nukleosidy MeSH
Nucleoside-based drugs, recognized as purine or pyrimidine analogs, have been potent therapeutic agents since their introduction in 1950, deployed widely in the treatment of diverse diseases such as cancers, myelodysplastic syndromes, multiple sclerosis, and viral infections. These antimetabolites establish complex interactions with cellular molecular constituents, primarily via activation of phosphorylation cascades leading to consequential interactions with nucleic acids. However, the therapeutic efficacy of these agents is frequently compromised by the development of drug resistance, a continually emerging challenge in their clinical application. This comprehensive review explores the mechanisms of resistance to nucleoside-based drugs, encompassing a wide spectrum of phenomena from alterations in membrane transporters and activating kinases to changes in drug elimination strategies and DNA damage repair mechanisms. The critical analysis in this review underlines complex interactions of drug and cell and also guides towards novel therapeutic strategies to counteract resistance. The development of targeted therapies, novel nucleoside analogs, and synergistic drug combinations are promising approaches to restore tumor sensitivity and improve patient outcomes.
- Klíčová slova
- ABC transporters, Cancer, Cancer therapy, Drug resistance, Metabolism, Nucleosides, SLC transporters,
- MeSH
- antimetabolity farmakologie MeSH
- léková rezistence MeSH
- lidé MeSH
- membránové transportní proteiny MeSH
- nádory * farmakoterapie MeSH
- nukleosidy farmakologie terapeutické užití MeSH
- protinádorové látky * farmakologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- antimetabolity MeSH
- membránové transportní proteiny MeSH
- nukleosidy MeSH
- protinádorové látky * MeSH
Twelve N2'-branched acyclic nucleoside phosphonates and bisphosphonates were synthesized as potential inhibitors of Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase (PfHGXPRT), the key enzyme in the purine salvage pathway for production of purine nucleotides. The chemical structures were designed with the aim to study selectivity of the inhibitors for PfHGXPRT over human HGPRT. The newly prepared compounds contain 9-deazahypoxanthine connected to a phosphonate group via a five-atom-linker bearing a nitrogen atom (N2') as a branching point. All compounds, with the additional phosphonate group(s) in the second aliphatic linker attached to N2' atom, were low micromolar inhibitors of PfHGXPRT with low to modest selectivity for the parasite enzyme over human HGPRT. The effect of the addition of different chemical groups/linkers to N2' atom on the inhibition constants and selectivity is discussed.
- Klíčová slova
- Acyclic nucleoside phosphonates, Plasmodium falciparum, hypoxanthine-guanine-(xanthine) phosphoribosyltransferase, inhibitors, malaria,
- MeSH
- antimalarika * farmakologie chemie MeSH
- hypoxanthinfosforibosyltransferasa metabolismus farmakologie MeSH
- hypoxanthiny farmakologie MeSH
- inhibitory enzymů farmakologie chemie MeSH
- lidé MeSH
- nukleosidy farmakologie chemie MeSH
- organofosfonáty * farmakologie chemie MeSH
- pentosyltransferasy MeSH
- Plasmodium falciparum MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 9-deazahypoxanthine MeSH Prohlížeč
- antimalarika * MeSH
- hypoxanthinfosforibosyltransferasa MeSH
- hypoxanthiny MeSH
- inhibitory enzymů MeSH
- nukleosidy MeSH
- organofosfonáty * MeSH
- pentosyltransferasy MeSH
The nucleoside analog entecavir (ETV) is a first-line pharmacotherapy for chronic hepatitis B in adult and pediatric patients. However, due to insufficient data on placental transfer and its effects on pregnancy, ETV administration is not recommended for women after conception. To expand knowledge of safety, we focused on evaluating the contribution of nucleoside transporters (NBMPR sensitive ENTs and Na+ dependent CNTs) and efflux transporters, P-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2), and multidrug resistance-associated transporter 2 (ABCC2), to the placental kinetics of ETV. We observed that NBMPR and nucleosides (adenosine and/or uridine) inhibited [3H]ETV uptake into BeWo cells, microvillous membrane vesicles, and fresh villous fragments prepared from the human term placenta, while Na+ depletion had no effect. Using a dual perfusion study in an open-circuit setup, we showed that maternal-to-fetal and fetal-to-maternal clearances of [3H]ETV in the rat term placenta were decreased by NBMPR and uridine. Net efflux ratios calculated for bidirectional transport studies performed in MDCKII cells expressing human ABCB1, ABCG2, or ABCC2 were close to the value of one. Consistently, no significant decrease in fetal perfusate was observed in the closed-circuit setup of dual perfusion studies, suggesting that active efflux does not significantly reduce maternal-to-fetal transport. In conclusion, ENTs (most likely ENT1), but not CNTs, ABCB1, ABCG2, and ABCC2, contribute significantly to the placental kinetics of ETV. Future studies should investigate the placental/fetal toxicity of ETV, the impact of drug-drug interactions on ENT1, and interindividual variability in ENT1 expression on the placental uptake and fetal exposure to ETV.
- Klíčová slova
- ATP-binding cassette transporters, Concentrative nucleoside transporters, Entecavir, Equilibrative nucleoside transporters, Placental transfer,
- MeSH
- ABC transportér z rodiny G, člen 2 metabolismus MeSH
- dítě MeSH
- krysa rodu Rattus MeSH
- lidé MeSH
- membránové transportní proteiny metabolismus MeSH
- nádorové proteiny metabolismus MeSH
- nádory prsu * metabolismus MeSH
- nukleosidy metabolismus farmakologie MeSH
- P-glykoprotein metabolismus MeSH
- P-glykoproteiny metabolismus MeSH
- placenta * metabolismus MeSH
- potkani Wistar MeSH
- protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
- proteiny přenášející nukleosidy metabolismus farmakologie MeSH
- proteiny spojené s mnohočetnou rezistencí k lékům metabolismus MeSH
- těhotenství MeSH
- uridin MeSH
- zvířata MeSH
- Check Tag
- dítě MeSH
- krysa rodu Rattus MeSH
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 4-nitrobenzylthioinosine MeSH Prohlížeč
- ABC transportér z rodiny G, člen 2 MeSH
- ABCB1 protein, human MeSH Prohlížeč
- ABCC2 protein, human MeSH Prohlížeč
- ABCG2 protein, human MeSH Prohlížeč
- entecavir MeSH Prohlížeč
- membránové transportní proteiny MeSH
- nádorové proteiny MeSH
- nukleosidy MeSH
- P-glykoprotein MeSH
- P-glykoproteiny MeSH
- protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
- proteiny přenášející nukleosidy MeSH
- proteiny spojené s mnohočetnou rezistencí k lékům MeSH
- uridin MeSH
A highly efficient and versatile synthetic approach for the synthesis of 4-(pyren-1-ylmethyl)-1-(d-glycosyloxy) phthalazine nucleosides 11a,b, 13, β-S-nucleosides 16, 18, 20, and acyclo C-nucleosides 23a,b, 24, 25 and 27a-f was described and fully characterized. Furthermore, a series of desired new nucleoside analogues containing Se of 4-(pyren-1-ylmethyl) phthalazine-1(2H)-selenone 28-33 were synthesized. The structures of all reported compounds were confirmed by IR, 1H-NMR, 13C-NMR, MS and elemental analysis. All compounds have been screened for their antibacterial and antifungal activities. Maximum activity was shown by 20 and 33a comparable to the standard drugs with lower toxicity. The cytotoxicity of the selected compound was measured and evaluated. The energy gap between the highest occupied molecular orbital and lowest unoccupied molecular orbital was calculated using theoretical computations to reflect the chemical reactivity and kinetic stability of the synthesized compounds. Using density functional theory (DFT), electronic parameters such as the highest occupied and lowest unoccupied molecular orbitals (HOMO and LUMO) and the molecular electrostatic potential (MEPS) were calculated. On the basis of different studied structures, these properties were computed in order to elucidate the chemical reactivity and the kinetic stability. Obviously, the band gap energy (Eg) of structures studied reveals that the lowest band gap obtained for the structure 16-a indicates that it has the highest chemical reactivity and lowest kinetic stability.
- Klíčová slova
- S-nucleosides, antibacterial, biocompatibility, mono/disaccharides, nucleoside analogues, quantum calculations,
- MeSH
- antibakteriální látky * farmakologie MeSH
- ftalaziny farmakologie MeSH
- kvantová teorie MeSH
- magnetická rezonanční spektroskopie MeSH
- molekulární modely MeSH
- nukleosidy * farmakologie MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antibakteriální látky * MeSH
- ftalaziny MeSH
- nukleosidy * MeSH
Purine nucleosides represent an interesting group of nitrogen heterocycles, showing a wide range of biological effects. In this study, we designed and synthesized a series of 6,9-disubstituted and 2,6,9-trisubstituted purine ribonucleosides via consecutive nucleophilic aromatic substitution, glycosylation, and deprotection of the ribofuranose unit. We prepared eight new purine nucleosides bearing unique adamantylated aromatic amines at position 6. Additionally, the ability of the synthesized purine nucleosides to form stable host-guest complexes with β-cyclodextrin (β-CD) was confirmed using nuclear magnetic resonance (NMR) and mass spectrometry (ESI-MS) experiments. The in vitro antiproliferative activity of purine nucleosides and their equimolar mixtures with β-CD was tested against two types of human tumor cell line. Six adamantane-based purine nucleosides showed an antiproliferative activity in the micromolar range. Moreover, their effect was only slightly suppressed by the presence of β-CD, which was probably due to the competitive binding of the corresponding purine nucleoside inside the β-CD cavity.
- Klíčová slova
- adamantane, antiproliferative activity, glycosylation, nucleoside, purine, β-cyclodextrin,
- MeSH
- adamantan * farmakologie MeSH
- beta-cyklodextriny * farmakologie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nukleosidy farmakologie chemie MeSH
- purinové nukleosidy farmakologie metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- adamantan * MeSH
- beta-cyklodextriny * MeSH
- nukleosidy MeSH
- purinové nukleosidy MeSH
d-Arabinofuranosyl-pyrimidine and -purine nucleoside analogues containing alkylthio-, acetylthio- or 1-thiosugar substituents at the C2' position were prepared from the corresponding 3',5'-O-silylene acetal-protected nucleoside 2'-exomethylenes by photoinitiated, radical-mediated hydrothiolation reactions. Although the stereochemical outcome of the hydrothiolation depended on the structure of both the thiol and the furanoside aglycone, in general, high d-arabino selectivity was obtained. The cytotoxic effect of the arabinonucleosides was studied on tumorous SCC (mouse squamous cell) and immortalized control HaCaT (human keratinocyte) cell lines by MTT assay. Three pyrimidine nucleosides containing C2'-butylsulfanylmethyl or -acetylthiomethyl groups showed promising cytotoxicity at low micromolar concentrations with good selectivity towards tumor cells. SAR analysis using a methyl β-d-arabinofuranoside reference compound showed that the silyl-protecting group, the nucleobase and the corresponding C2' substituent are crucial for the cell growth inhibitory activity. The effects of the three most active nucleoside analogues on parameters indicative of cytotoxicity, such as cell size, division time and cell generation time, were investigated by near-infrared live cell imaging, which showed that the 2'-acetylthiomethyluridine derivative induced the most significant functional and morphological changes. Some nucleoside analogues also exerted anti-SARS-CoV-2 and/or anti-HCoV-229E activity with low micromolar EC50 values; however, the antiviral activity was always accompanied by significant cytotoxicity.
- Klíčová slova
- SARS-CoV-2, anti-tumor, antiviral, coronavirus, nucleoside analogue, photocatalytic thiol-ene reaction, time-lapse imaging,
- MeSH
- acetaly MeSH
- antivirové látky farmakologie MeSH
- arabinonukleosidy chemie farmakologie MeSH
- COVID-19 * MeSH
- lidé MeSH
- myši MeSH
- nukleosidy farmakologie chemie MeSH
- puriny MeSH
- pyrimidinové nukleosidy * MeSH
- sulfhydrylové sloučeniny chemie MeSH
- thiosacharidy * MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- acetaly MeSH
- antivirové látky MeSH
- arabinonukleosidy MeSH
- nukleosidy MeSH
- puriny MeSH
- pyrimidinové nukleosidy * MeSH
- sulfhydrylové sloučeniny MeSH
- thiosacharidy * MeSH
A series of novel 7-aryl-7-deazaadenine-based N-branched acyclic nucleoside phosphonates (aza-ANPs) has been prepared using the optimized Suzuki cross-coupling reaction as the key synthetic step. The final free phosphonates 15a-h were inactive, due to their inefficient transport across cell membranes, but they inhibited Trypanosoma brucei adenine phosphoribosyltransferase (TbrAPRT1) with Ki values of 1.7-14.1 μM. The corresponding phosphonodiamidate prodrugs 14a-h exhibited anti-trypanosomal activity in the Trypanosoma brucei brucei cell-based assay with EC50 values in the range of 0.58-6.8 μM. 7-(4-Methoxy)phenyl-7-deazapurine derivative 14h, containing two phosphonate moieties, was the most potent anti-trypanosomal agent from the series, with EC50 = 0.58 μM and SI = 16. Finally, phosphonodiamidate prodrugs 14a-h exerted low micromolar cytotoxicity against leukemia and/or cancer cell lines tested.
- Klíčová slova
- Acyclic nucleoside phosphonates, Nucleotides, Suzuki reaction, Trypanosoma, Tubercidin,
- MeSH
- nukleosidy farmakologie MeSH
- organofosfonáty * farmakologie MeSH
- prekurzory léčiv * farmakologie MeSH
- puriny MeSH
- Trypanosoma brucei brucei * MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- 7-deazapurine MeSH Prohlížeč
- nukleosidy MeSH
- organofosfonáty * MeSH
- prekurzory léčiv * MeSH
- puriny MeSH
Histone methyltransferase DOT1L is an attractive therapeutic target for the treatment of hematological malignancies. Here, we report the design, synthesis, and profiling of new DOT1L inhibitors based on nonroutine carbocyclic C-nucleoside scaffolds. The experimentally observed SAR was found to be nontrivial as seemingly minor changes of individual substituents resulted in significant changes in the affinity to DOT1L. Molecular modeling suggested that these trends could be related to significant conformational changes of the protein upon interaction with the inhibitors. The compounds 22 and (-)-53 (MU1656), carbocyclic C-nucleoside analogues of the natural nucleoside derivative EPZ004777, and the clinical candidate EPZ5676 (pinometostat) potently and selectively inhibit DOT1L in vitro as well as in the cell. The most potent compound MU1656 was found to be more metabolically stable and significantly less toxic in vivo than pinometostat itself.
